. A critical challenge for aging research today is to define strategies for "healthy aging". Studies in invertebrate models are contributing heavily to this effort by providing novel mechanistic insight into conserved processes relevant to healthspan biology. microRNAs (miRNAs) are small molecules that execute a newly discovered, yet highly prevalent, gene regulatory function. Next to nothing is known about how miRNAs affect the biology of aging, although very recent work has shown that miRNA lin-4 affects lifespan and age pigment accumulation rates. We have characterized the expression of all 114 C. elegans miRNAs during adult lifespan and find that the levels of several miRNAs rise or fall in patterns consistent with potential roles in aging and healthspan modulation. Our plan is to exploit the experimental advantages of the C. elegans system to define the roles of age-regulated miRNAs in the biology of aging, with an emphasis on those that impact overall healthspan and sarcopenia (age-related muscle decline, a conserved problem in aging biology with tremendous impact on human healthspan). Aim 1 is to define the role of mir-1 on age-related decline of muscle. We will test the hypothesis that changes in the levels of specific conserved muscle miRNA mir-1 (the decline of which parallels age-related muscle decline in adults) influences muscle aging, and that manipulation of mir-1 levels later in life could extend muscle healthspan. This study could provide the first detail on how a miRNA can affect muscle aging and could establish proof-of-principle for novel therapies for extension of muscle healthspan. Aim 2 is to identify age-regulated miRNAs that influence aging and healthspan. We will address more broadly the roles that age-regulated miRNAs play in aging by testing how their over-expression and deletion affects lifespan and healthspan. Our work will provide the first genome-wide documentation of age-regulated miRNAs on aging. Since many miRNAs are conserved in expression pattern and function, we anticipate that our exploratory work in this area will be of high impact and will suggest specific working hypotheses for mammalian aging, perhaps suggesting novel means of clinical intervention. Since we will place major emphasis on miRNAs with human homologs, our work should hold considerable significance and potential for extending healthspan. [unreadable] [unreadable] [unreadable] [unreadable]